Pompeu Fabra University

About: Pompeu Fabra University is a education organization based out in Barcelona, Spain. It is known for research contribution in the topics: Population & Context (language use). The organization has 8093 authors who have published 23570 publications receiving 858431 citations. The organization is also known as: Universitat Pompeu Fabra & UPF.

Multi-domain conformational selection underlies pre-mRNA splicing regulation by U2AF

Abstract: Different domains of a protein can interact dynamically to recognize a ligand, but the coordination of binding by multiple domains is not well understood. Michael Sattler and colleagues have investigated binding of a polypurine tract RNA by tandem RNA recognition motifs (RRMs) of a splicing factor. The domains exist in equilibrium between two distinct conformations, which shifts based on the affinity of the tract for the RRMs. This work highlights the role that cooperative multi-domain conformational selection can have when sequence specificity is not strict. Many cellular functions involve multi-domain proteins, which are composed of structurally independent modules connected by flexible linkers. Although it is often well understood how a given domain recognizes a cognate oligonucleotide or peptide motif, the dynamic interaction of multiple domains in the recognition of these ligands remains to be characterized. Here we have studied the molecular mechanisms of the recognition of the 3′-splice-site-associated polypyrimidine tract RNA by the large subunit of the human U2 snRNP auxiliary factor (U2AF65)1,2,3 as a key early step in pre-mRNA splicing4. We show that the tandem RNA recognition motif domains of U2AF65 adopt two remarkably distinct domain arrangements in the absence or presence of a strong (that is, high affinity) polypyrimidine tract. Recognition of sequence variations in the polypyrimidine tract RNA involves a population shift between these closed and open conformations. The equilibrium between the two conformations functions as a molecular rheostat that quantitatively correlates the natural variations in polypyrimidine tract nucleotide composition, length and functional strength to the efficiency to recruit U2 snRNP to the intron during spliceosome assembly1,5,6,7,8. Mutations that shift the conformational equilibrium without directly affecting RNA binding modulate splicing activity accordingly. Similar mechanisms of cooperative multi-domain conformational selection may operate more generally in the recognition of degenerate nucleotide or amino acid motifs by multi-domain proteins9,10.

Balancing Selection Is the Main Force Shaping the Evolution of Innate Immunity Genes

Abstract: The evolutionarily recent geographic expansion of humans, and the even more recent development of large, relatively dense human settlements, has exposed our species to new pathogenic environments. Potentially lethal pathogens are likely to have exerted important selective pressures on our genome, so immunity genes can be expected to show molecular signatures of the adaptation of human populations to these recent conditions. While genes related to the acquired immunity system have indeed been reported to show traces of local adaptation, little is known about the response of the innate immunity system. In this study, we analyze the variability patterns in different human populations of fifteen genes related to innate immunity. We have used both single nucleotide polymorphism and sequence data, and through the analysis of interpopulation differentiation, the linkage disequilibrium pattern, and intrapopulation diversity, we have discovered some signatures of positive and especially balancing selection in these genes, thus confirming the importance of the immune system genetic plasticity in the evolutionary adaptive process. Interestingly, the strongest evidence is found in three TLR genes and CD14. These innate immunity genes play a pivotal role, being involved in the primary recognition of pathogens. In general, more evidences of selection appear in the European populations, in some case possibly related to severe population specific pressures. However, we also describe evidence from African populations, which may reflect parallel or long-term selective forces acting in different geographic areas.

The genomic landscape of meiotic crossovers and gene conversions in Arabidopsis thaliana

Abstract: Knowledge of the exact distribution of meiotic crossovers (COs) and gene conversions (GCs) is essential for understanding many aspects of population genetics and evolution, from haplotype structure and long-distance genetic linkage to the generation of new allelic variants of genes. To this end, we resequenced the four products of 13 meiotic tetrads along with 10 doubled haploids derived from Arabidopsis thaliana hybrids. GC detection through short reads has previously been confounded by genomic rearrangements. Rigid filtering for misaligned reads allowed GC identification at high accuracy and revealed an ∼80-kb transposition, which undergoes copy-number changes mediated by meiotic recombination. Non-crossover associated GCs were extremely rare most likely due to their short average length of ∼25-50 bp, which is significantly shorter than the length of CO-associated GCs. Overall, recombination preferentially targeted non-methylated nucleosome-free regions at gene promoters, which showed significant enrichment of two sequence

A behavioural model to reveal place preference to Δ9-tetrahydrocannabinol in mice

Abstract: Rationale: The rewarding properties of Δ9- tetrahydrocannabinol (THC) are difficult to demonstrate in rodents using standard procedures. Objective: To evaluate the motivational responses of THC in the place conditioning paradigm in mice after minimizing the dysphoric effects of the first drug exposure and/or the consequences of its pharmacokinetic properties. Methods: Mice were conditioned to THC (1 or 5 mg/kg) using an unbiased procedure with an elevated number of pairings and long conditioning time. Results: A place aversion was observed with 5 mg/kg THC using a standard protocol. Similar results were obtained when the CB-1 receptor antagonist SR 141716A (1 mg/kg) was administered immediately after each THC conditioning period. However, mice receiving a priming THC injection and conditioned 24 h later showed a place preference with 1 mg/kg THC and no effect with 5 mg/kg THC. Conclusion: THC produces a clear place preference in mice by using a long period of conditioning and avoiding the possible dysphoric consequences of the first drug exposure.

Socioeconomic inequalities in diabetes mellitus across Europe at the beginning of the 21st century

Abstract: Aims/hypothesis The aim of this study was to determine and quantify socioeconomic position (SEP) inequalities in diabetes mellitus in different areas of Europe, at the turn of the century, for men and women.